Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 18 de 18
Filter
Add more filters










Publication year range
1.
Pathol Oncol Res ; 26(3): 1583-1594, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31489573

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma with high metastatic rate and high mortality rate, needing to find potential therapeutic targets and develop new therapy methods. The bioinformatics analysis was used in this study to find the targets. Firstly, the expression profile of ccRCC obtained from The Cancer Genome Atlas (TCGA) database and GSE53757 dataset were used to identify the significant up-regulated genes. IL20RB, AURKB and KIF18B with the top efficiency of capable of diagnosis ccRCC from para cancer tissue, were over-expressed in ccRCC samples, and expressed increasedly with the development of ccRCC. There was the closest correlation between AURKB and KIF18B in these three over-expressed genes. AURKB (high) or KIF18B (high) were all significantly correlated with higher T, N, M stage, G grade and shorter overall survival (OS) of ccRCC patients. Furthermore, the ccRCC patients with AURKB (high) + KIF18B (high) showed worse clinical characteristics and prognosis. Multivariate COX regression analysis indicated AURKB (high) and KIF18B (high) were all the independent prognostic risk factor without considering the interaction of AURKB and KIF18B. Moreover, considering the combination of each other, only AURKB (high) + KIF18B (high) expression was an independent prognostic risk factor for ccRCC patients, but not other situations. Collectively, AURKB was closely associated with KIF18B, and the combined expression of AURKB and KIF18B may be of great significance in ccRCC.


Subject(s)
Aurora Kinase B/biosynthesis , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Kinesins/biosynthesis , Adult , Aged , Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/metabolism , Computational Biology/methods , Female , Gene Expression Profiling/methods , Humans , Kidney Neoplasms/metabolism , Male , Middle Aged , Prognosis , Transcriptome
2.
Anticancer Drugs ; 30(1): 19-26, 2019 01.
Article in English | MEDLINE | ID: mdl-30540594

ABSTRACT

Barasertib is a highly selective Aurora kinase B (AURKB) inhibitor and has been widely applied in a variety of cancer cells to investigate the regulatory function of AURKB. However, the effect of barasertib on glucose metabolism in gastric cancer (GC) remains illustrated. Here, barasertib was identified to effectively reduce glucose uptake and lactate production in GC cells in a dose-dependent and time-dependent manner. The expression levels of GLUT1, LDHA and HK2 were decreased by barasertib treatment of GC cells. Furthermore, we found that barasertib induced the expression of ribosomal protein S7 (RPS7), as a tumor suppressor, to regulate glucose metabolism. Silencing of RPS7 rescued the effects of barasertib on glucose metabolism in GC cells. Overexpression of RPS7 suppressed the promoter activity of C-Myc, which has been identified as an important regulator of glucose metabolism in cancer cells. The clinical data showed that the expression level of AURKB in GC patients' sera and tissues were positively correlated with those of C-Myc, GLUT1 and LDHA, but negatively with that of RPS7. Therefore, these findings provide new evidence that barasertib regulates GC cell glucose metabolism by inducing the RPS7/C-Myc signal pathway, and have important implications for the development of therapeutic approaches using AURKB as a target protein to prevent tumor recurrence.


Subject(s)
Aurora Kinase B/antagonists & inhibitors , Glucose/metabolism , Organophosphates/pharmacology , Quinazolines/pharmacology , Stomach Neoplasms/drug therapy , Aurora Kinase B/biosynthesis , Case-Control Studies , Cell Line, Tumor , Dose-Response Relationship, Drug , Glucose Transporter Type 1/metabolism , Humans , Isoenzymes/metabolism , L-Lactate Dehydrogenase/metabolism , Promoter Regions, Genetic , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Ribosomal Proteins/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism
3.
Int J Cancer ; 141(8): 1643-1653, 2017 10 15.
Article in English | MEDLINE | ID: mdl-28670704

ABSTRACT

Cyclin K plays a critical role in transcriptional regulation as well as cell development. However, the role of Cyclin K in prostate cancer is unknown. Here, we describe the impact of Cyclin K on prostate cancer cells and examine the clinical relevance of Cyclin K as a biomarker for patients with prostate cancer. We show that Cyclin K depletion in prostate cancer cells induces apoptosis and inhibits proliferation accompanied by an accumulation of cells in the G2/M phase. Moreover, knockdown of Cyclin K causes mitotic catastrophe displayed by multinucleation and spindle multipolarity. Furthermore, we demonstrate a Cyclin K dependent regulation of the mitotic kinase Aurora B and provide evidence for an Aurora B dependent induction of mitotic catastrophe. In addition, we show that Cyclin K expression is associated with poor biochemical recurrence-free survival in patients with prostate cancer treated with an adjuvant therapy. In conclusion, targeting Cyclin K represents a novel, promising anti-cancer strategy to induce cell cycle arrest and apoptotic cell death through induction of mitotic catastrophe in prostate cancer cells. Moreover, our results indicate that Cyclin K is a putative predictive biomarker for clinical outcome and therapy response for patients with prostate cancer.


Subject(s)
Aurora Kinase B/metabolism , Cyclins/metabolism , Prostatic Neoplasms/pathology , Apoptosis/physiology , Aurora Kinase B/biosynthesis , Aurora Kinase B/genetics , Cell Cycle/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Cyclins/deficiency , Cyclins/genetics , Humans , Male , Mitosis/physiology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism
4.
Carcinogenesis ; 37(10): 993-1003, 2016 10.
Article in English | MEDLINE | ID: mdl-27515963

ABSTRACT

The mitotic Aurora B kinase is overexpressed in tumors and various inhibitors for Aurora B are currently under clinical assessments. However, when considering Aurora B kinase inhibitors as anticancer drugs, their mode of action and the role of p53 status as a possible predictive factor for response still needs to be investigated. In this study, we analyzed the effects of selective Aurora B inhibition using AZD1152-HQPA/Barasertib (AZD1152) on HCT116 cells, U87-MG, corresponding isogenic p53-deficient cells and a primary glioblastoma cell line. AZD1152 treatment caused polyploidy and non-apoptotic cell death in all cell lines irrespective of p53 status and was accompanied by poly-merotelic kinetochore-microtubule attachments and DNA damage. In p53 wild-type cells a DNA damage response induced an inefficient pseudo-G1 cell cycle arrest, which was not able to halt ongoing endoreplication of cells. Of note, release of tumor cells from AZD1152 resulted in recovery of aneuploid progenies bearing numerical and structural chromosomal aberrations. Yet, AZD1152 treatment enhanced death receptor TRAIL-R2 levels in all tumor cell lines investigated. A concomitant increase of the activating natural killer (NK) cell ligand MIC A/B in p53-deficient cells and an induction of FAS/CD95 in cells containing p53 rendered AZD1152-treated cells more susceptible for NK-cell-mediated lysis. Our study mechanistically explains a p53-independent mode of action of a chemical Aurora B inhibitor and suggests a potential triggering of antitumoral immune responses, following polyploidization of tumor cells, which might constrain recovery of aneuploid tumor cells.


Subject(s)
Apoptosis/drug effects , Aurora Kinase B/biosynthesis , Cell Proliferation/drug effects , Tumor Suppressor Protein p53/genetics , Aneuploidy , Aurora Kinase B/antagonists & inhibitors , Cell Cycle Checkpoints/drug effects , Chromosome Aberrations/drug effects , DNA Damage/drug effects , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , Humans , Organophosphates/administration & dosage , Quinazolines/administration & dosage , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Tumor Suppressor Protein p53/biosynthesis
5.
Ann Hematol ; 95(7): 1031-42, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27091351

ABSTRACT

Aurora B kinase as a chromosomal passenger protein plays multiple roles in regulating mitosis and cytokinesis. The function of Aurora B in leukemic cells has made it an important treatment target. In this study, we explored the expressions of Aurora (A, B, and C) kinases in newly diagnosed acute promyelocytic leukemia (APL) patients. In addition, we investigated the effects of AZD1152 as a specific inhibitor of Aurora B on cell survival, DNA synthesis, nuclear morphology, apoptosis induction, cell cycle distribution, and gene expression in an APL-derived NB4 cell line. Our results showed that Aurora B was overexpressed in 88 % of APL patients. AZD1152 treatment of NB4 cells led to viability reduction and G2/M arrest followed by an increase in cell size and polyploidy induction. These giant cells showed morphological evidence of mitotic catastrophe. AZD1152 treatment induced activation of G2/M checkpoint which in turn led to transient G2/M arrest in a p21-independent manner. Lack of functional p53 in NB4 cells might provide an opportunity to escape from G2/M block and to endure repeated rounds of replication and polyploidy. Treated cells were probably eliminated via p73-mediated overexpression of BAX, PUMA, and APAF1 and downregulation of survivin and MCL-1. In summary, AZD1152 treatment led to endomitosis and polyploidy in TP53-mutated NB4 cells. These giant polyploid cells might undergo mitotic catastrophe and p73-mediated apoptosis. It seems that induction of polyploidy via AZD1152 could be a novel form of anti-cancer therapy for APL that may be clinically accessible in the near future.


Subject(s)
Aurora Kinase B/antagonists & inhibitors , Aurora Kinase B/biosynthesis , Gene Expression Regulation, Neoplastic , Leukemia, Promyelocytic, Acute/drug therapy , Organophosphates/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Adult , Aurora Kinase B/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/physiology , Dose-Response Relationship, Drug , Female , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/metabolism , Male , Middle Aged , Organophosphates/pharmacology , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Treatment Outcome
6.
J Biomed Sci ; 22: 48, 2015 Jul 04.
Article in English | MEDLINE | ID: mdl-26141684

ABSTRACT

BACKGROUND: Breast cancer is classified into three subtypes by the expression of biomarker receptors such as hormone receptors and human epidermal growth factor receptor 2. Triple-negative breast cancer (TNBC) expresses none of these receptors and has an aggressive phenotype with a poor prognosis, which is insensitive to the drugs that target the hormone receptors and human epidermal growth factor receptor 2. It is, thus, required to develop an effective therapeutic reagent to treat TNBC. RESULTS: The study using a panel of 19 breast cancer cell lines revealed that midostaurin, a multi-target protein kinase inhibitor, suppresses preferentially the growth of TNBC cells comparing with non-TNBC cells. Clustering analysis of the drug activity data for the panel of cancer cell lines predicted that midostaurin shares the target with Aurora kinase inhibitors. Following studies indicated that midostaurin attenuates the phosphorylation reaction mediated by Aurora kinase in the cells and directly inhibits this protein kinase in vitro, and that this reagent induces apoptosis accompanying accumulation of 4N and 8N DNA cells in TNBC cells. CONCLUSION: Midostaurin suppresses the proliferation of TNBC cells among the breast cancer cell lines presumably through the inhibition of the Aurora kinase family. The precise study of midostaurin on cell growth will contribute to the development of the drug for the treatment of TNBC.


Subject(s)
Aurora Kinase A/biosynthesis , Aurora Kinase B/biosynthesis , Staurosporine/analogs & derivatives , Triple Negative Breast Neoplasms/drug therapy , Animals , Apoptosis/drug effects , Aurora Kinase A/genetics , Aurora Kinase B/genetics , Cell Proliferation/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Mice , Protein Kinase Inhibitors/administration & dosage , Staurosporine/administration & dosage , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays
7.
Oncol Rep ; 34(2): 803-10, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26044736

ABSTRACT

The Aurora kinase family of serine/threonine kinases are known to be crucial for cell cycle control. Aurora kinases are considered a target of anticancer drugs. However, few studies have assessed the effect of Aurora kinases in breast cancer. In the present study, to determine whether Aurora kinases play a role in oncogenic actions of protein kinase C (PKC), we investigated the effect of Aurora kinases on PKC-induced invasion and MMP-9 expression using breast cancer cells. Treatment of MCF-7 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced the upregulation and phosphorylation of Aurora kinases via the MAPK signaling pathway. Moreover, the inhibition of Aurora kinases by their siRNAs and inhibitors suppressed TPA-induced cell invasion and expression of MMP-9 by inhibiting the activation of NF-κB/AP-1, major transcription factors for MMP-9 expression in MCF-7 cells. These results suggested that Aurora kinases mediate PKC-MAPK signal to NF-κB/AP-1 with increasing MMP-9 expression and invasion of MCF-7 cells. To the best of our knowledge, this is the first study to show that Aurora kinases are key molecules in PKC-induced invasion in breast cancer cells.


Subject(s)
Aurora Kinase A/biosynthesis , Aurora Kinase B/biosynthesis , Breast Neoplasms/genetics , Matrix Metalloproteinase 9/biosynthesis , Protein Kinase C/biosynthesis , Aurora Kinase A/genetics , Aurora Kinase B/genetics , Breast Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Matrix Metalloproteinase 9/genetics , Mitogen-Activated Protein Kinase Kinases/genetics , NF-kappa B/biosynthesis , NF-kappa B/genetics , Neoplasm Invasiveness/genetics , Protein Kinase C/genetics , Signal Transduction/drug effects , Tetradecanoylphorbol Acetate/pharmacology
8.
Tumour Biol ; 36(5): 3895-902, 2015 May.
Article in English | MEDLINE | ID: mdl-25874486

ABSTRACT

The aim of this study is to investigate the effects of inhibiting Aurora-B on osteosarcoma (OS) cell malignant phenotype, phosphorylation of valosin-containing protein (VCP), and the activity of NF-κB signaling in vitro. The expressions of Aurora-B and p-VCP proteins were detected by immunohistochemistry in 24 OS tissues, and the relationship between Aurora-B and p-VCP was investigated. The results showed that there was a positive correlation between Aurora-B and p-VCP proteins. The expression of Aurora-B in human OS cell lines U2-OS and HOS cells was inhibited by specific short hairpin RNA (shRNA) lentivirus (AURKB-shRNA lentivirus, Lv-shAURKB) which targeted Aurora-B. The results showed that the phosphorylation of VCP, the activity of NF-κB signaling pathway and the malignant phenotype of OS cells were all suppressed by knockdown of Aurora-B. It indicated that the inhibition of Aurora-B alters OS cells malignant phenotype by downregulating phosphorylation of VCP and activating of the NF-κB signaling pathway in vitro.


Subject(s)
Adenosine Triphosphatases/biosynthesis , Aurora Kinase B/genetics , Bone Neoplasms/genetics , Cell Cycle Proteins/biosynthesis , NF-kappa B/genetics , Osteosarcoma/genetics , Adenosine Triphosphatases/genetics , Apoptosis/genetics , Aurora Kinase B/biosynthesis , Bone Neoplasms/pathology , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Osteosarcoma/pathology , Phosphorylation , Signal Transduction/genetics , Valosin Containing Protein
9.
Int J Clin Exp Pathol ; 8(1): 751-7, 2015.
Article in English | MEDLINE | ID: mdl-25755770

ABSTRACT

Aurora-B is a major kinase responsible for appropriate mitotic progression. Elevated expression of Aurora-B has been frequently associated with several types of cancer, including breast cancer. However, it is not clear whether the alteration contributes to tumor responses to therapies and prognosis. In this study, we conducted immunohistochemistry using antibodies against Aurora-B, S1981p-ATM, Ki67, and p53 in paraffin-embedded tumor tissues from 312 invasive breast cancer patients. The correlation between disease-free-survival (DFS) and Aurora-B expression was analyzed using the Kaplan-Meier method and log-rank test. A Cox proportional hazards regression analysis was used to determine whether Aurora-B was an independent prognostic factor for breast cancer. We found that Aurora-B expression was correlated with the proliferation index (P < 0.001) and p53 expression (P = 0.014) in breast cancer tissues. Further we found that Aurora-B expression was associated with lymph node metastasis (P = 0.002) and histological grade (P = 0.001). Multivariate analyses indicated that elevated Aurora-B expression predicted a poor survival. In a subgroup of patients that received neoadjuvant chemotherapy, we found that elevated Aurora-B contributed to chemoresistance (P = 0.011). In conclusion, elevated Aurora-B expression in breast cancer patients contributes to chemoresistance and predicts poor prognosis.


Subject(s)
Aurora Kinase B/biosynthesis , Biomarkers, Tumor/analysis , Breast Neoplasms/pathology , Drug Resistance, Neoplasm/physiology , Adult , Aged , Aged, 80 and over , Aurora Kinase B/analysis , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Disease-Free Survival , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Prognosis , Proportional Hazards Models
10.
Breast Cancer Res Treat ; 149(3): 715-26, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25667100

ABSTRACT

Aromatase inhibitors (AIs) are used for treatment of estrogen receptor α (ER)-positive breast cancer; however, resistance is a major obstacle for optimal outcome. This preclinical study aimed at identifying potential new treatment targets in AI-resistant breast cancer cells. Parental MCF-7 breast cancer cells and four newly established cell lines, resistant to the AIs exemestane or letrozole, were used for a functional kinase inhibitor screen. A library comprising 195 different compounds was tested for preferential growth inhibition of AI-resistant cell lines. Selected targets were validated by analysis of cell growth, cell cycle phase distribution, protein expression, and subcellular localization. We identified 24 compounds, including several inhibitors of Aurora kinases e.g., JNJ-7706621 and barasertib. Protein expression of Aurora kinase A and B was found upregulated in AI-resistant cells compared with MCF-7, and knockdown studies showed that Aurora kinase A was essential for AI-resistant cell growth. In AI-resistant cell lines, the clinically relevant Aurora kinase inhibitors alisertib and danusertib blocked cell cycle progression at the G2/M phase, interfered with chromosome alignment and spindle pole formation, and resulted in preferential growth inhibition compared with parental MCF-7 cells. Even further growth inhibition was obtained when combining the Aurora kinase inhibitors with the antiestrogen fulvestrant. Our study is the first to demonstrate that Aurora kinase A and B may be treatment targets in AI-resistant cells, and our data suggest that therapy targeting both ER and Aurora kinases may be a potent treatment strategy for overcoming AI resistance in breast cancer.


Subject(s)
Aromatase Inhibitors/administration & dosage , Aurora Kinase A/genetics , Aurora Kinase B/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Aurora Kinase A/biosynthesis , Aurora Kinase B/biosynthesis , Breast Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , Estrogen Receptor alpha/antagonists & inhibitors , Estrogen Receptor alpha/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Humans , MCF-7 Cells , Organophosphates/administration & dosage , Quinazolines/administration & dosage , Small Molecule Libraries/administration & dosage , Triazoles/administration & dosage
11.
Virchows Arch ; 466(5): 503-15, 2015 May.
Article in English | MEDLINE | ID: mdl-25680570

ABSTRACT

Experimental model systems identified phosphorylation of linker histone variant H1.4 at Ser 27 (H1.4S27p) as a novel mitotic mark set by Aurora B kinase. Here, we examined expression of Aurora B and H1.4S27p in colorectal carcinoma (CRC) cell lines (HCT116, DLD1, Caco-2, HT29) and tissue specimens (n = 36), in relation to microsatellite instability (MSI) status and ploidy. In vitro, Aurora B (pro-/meta-/anaphase) and H1.4S27p (pro-/metaphase) were localized in mitotic figures. The proportion of labeled mitoses was significantly different between cell lines for Aurora B (p = 0.019) but not for H1.4S27p (p = 0.879). For Aurora B, these differences were not associated with an altered Aurora B gene copy number (FISH) or messenger RNA (mRNA) expression level (qRT-PCR). Moreover, Aurora B expression and H1.4S27 phosphorylation were no longer coordinated during metaphase in aneuploid HT29 cells (p = 0.039). In CRCs, immunoreactivity for Aurora B or H1.4S27p did not correlate with T- or N-stage, grade, or MSI status. However, metaphase labeling of H1.4S27p was significantly higher in diploid than in aneuploid CRCs (p = 0.011). Aurora B was significantly correlated with H1.4S27p-positive metaphases in MSI (p = 0.010) or diploid (p = 0.003) CRCs. Finally, combined classification of MSI status and ploidy revealed a significant positive correlation of Aurora B with H1.4S27p in metaphases of diploid/MSI (p = 0.010) and diploid/microsatellite-stable (MSS; p = 0.031) but not of aneuploid/MSS (p = 0.458) CRCs. The present study underlines the functional link of Aurora B expression and H1.4S27p during specific phases of mitosis in diploid and/or MSI-positive CRCs in vitro and in situ. Importantly, the study shows that the coordination between Aurora B expression and phosphorylation of H1.4 at Ser 27 is lost in cycling aneuploid CRC cells.


Subject(s)
Adenocarcinoma/enzymology , Adenocarcinoma/genetics , Aurora Kinase B/biosynthesis , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/genetics , Histones/metabolism , Aneuploidy , Fluorescent Antibody Technique , Humans , In Situ Hybridization, Fluorescence , Metaphase , Microsatellite Instability , Phosphorylation
12.
Oncotarget ; 6(8): 5788-803, 2015 Mar 20.
Article in English | MEDLINE | ID: mdl-25691063

ABSTRACT

In multicellular organisms p53 maintains genomic integrity through activation of DNA repair, and apoptosis. EBNA3C can down regulate p53 transcriptional activity. Aurora kinase (AK) B phosphorylates p53, which leads to degradation of p53. Aberrant expression of AK-B is a hallmark of numerous human cancers. Therefore changes in the activities of p53 due to AK-B and EBNA3C expression is important for understanding EBV-mediated cell transformation. Here we show that the activities of p53 and its homolog p73 are dysregulated in EBV infected primary cells which can contribute to increased cell transformation. Further, we showed that the ETS-1 binding site is crucial for EBNA3C-mediated up-regulation of AK-B transcription. Further, we determined the Ser 215 residue of p53 is critical for functional regulation by AK-B and EBNA3C and that the kinase domain of AK-B which includes amino acid residues 106, 111 and 205 was important for p53 regulation. AK-B with a mutation at residue 207 was functionally similar to wild type AK-B in terms of its kinase activities and knockdown of AK-B led to enhanced p73 expression independent of p53. This study explores an additional mechanism by which p53 is regulated by AK-B and EBNA3C contributing to EBV-induced B-cell transformation.


Subject(s)
Aurora Kinase B/biosynthesis , Epstein-Barr Virus Nuclear Antigens/metabolism , Tumor Suppressor Protein p53/genetics , Antigens, Viral , Aurora Kinase B/genetics , Cell Line , Cell Proliferation/physiology , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Enzyme Induction , Epstein-Barr Virus Nuclear Antigens/genetics , Gene Knockout Techniques , HEK293 Cells , Humans , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Phosphorylation , Transfection , Tumor Protein p73 , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/genetics , Viral Proteins
13.
Tumour Biol ; 36(2): 623-32, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25277659

ABSTRACT

Prostate cancer is the frequent non-cutaneous tumor with high mortality in men. Prostate tumors contain cells with different status of androgen receptor. Androgen receptor plays important roles in progression and treatment of prostate cancer. Aurora B kinase, with oncogenic potential, is involved in chromosome segregation and cytokinesis, and its inhibition is a promising anti-cancer therapy. In the present study, we aimed to investigate the effects of Aurora B inhibitor, AZD1152-HQPA, on survival and proliferation of androgen receptor (AR)-positive prostate cancer cells. LNCaP was used as androgen-dependent prostate cancer cell line. We explored the effects of AZD1152-HQPA on cell viability, DNA content, micronuclei formation, and expression of genes involved in apoptosis and cell cycle. Moreover, the expression of Aurora B and AR were investigated in 23 benign prostatic hyperplasia and 38 prostate cancer specimens. AZD1152-HQPA treatment induced defective cell survival, polyploidy, and cell death in LNCaP cell line. Centromeric labeling with fluorescence in situ hybridization (FISH) showed that the loss of whole chromosomes is the origin of micronuclei, indicating on aneugenic action of AZD1152-HQPA. Treatment of AZD1152-HQPA decreased expression of AR. Moreover, we found weak positive correlations between the expression of Aurora B and AR in both benign prostatic hyperplasia and prostate cancer specimens (r = 0.25, r = 0.41). This is the first time to show that AZD1152-HQPA can be a useful therapeutic strategy for the treatment of androgen-dependent prostate cancer cell line. AZD1152-HQPA induces aneugenic mechanism of micronuclei production. Taken together, this study provides new insight into the direction to overcome the therapeutic impediments against prostate cancer.


Subject(s)
Aurora Kinase B/biosynthesis , Organophosphates/administration & dosage , Prostatic Neoplasms/drug therapy , Quinazolines/administration & dosage , Receptors, Androgen/biosynthesis , Aneugens/administration & dosage , Animals , Apoptosis/drug effects , Aurora Kinase B/genetics , Cell Line, Tumor , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , In Situ Hybridization, Fluorescence , Male , Mice , Micronuclei, Chromosome-Defective/drug effects , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Receptors, Androgen/genetics , Xenograft Model Antitumor Assays
14.
Int J Clin Exp Pathol ; 7(8): 4596-606, 2014.
Article in English | MEDLINE | ID: mdl-25197332

ABSTRACT

Accumulating studies revealed that the expression levels of several miRNAs are up or down-regulated in osteosarcoma (OS). The aim of this study was to investigate the functional significance and molecular of the let-7g in OS cells. The expression levels of let-7g was significantly down-regulated in OS cell lines U2-OS and HOS cell compared to osteoblast cell lines HOB cell. Moreover, bioinformatic prediction suggested that Aurora-B, which is overexpressed and functions as an oncogene in OS cells, is a putative target gene of let-7g. Using mRNA and protein expression analysis and luciferase assays, we further identified let-7g directly regulated Aurora-B expression in OS cells. Functional investigation revealed both restoration of let-7g and silencing Aurora-B induce cell apoptosis and suppressed cell viability, migratory and invasive ability in OS cells. Finally, we found that silencing Aurora-B in OS cells could partly dampen anti-let-7g mediated tumor promotion. Thus, our findings suggested that let-7g inhibits OS cell malignant phenotype at least partly through targeting Aurora-B. Targeting of let-7g and Aurora-B may be a novel therapeutic strategy for treating OS.


Subject(s)
Aurora Kinase B/biosynthesis , Bone Neoplasms/genetics , Gene Expression Regulation, Neoplastic/genetics , MicroRNAs/genetics , Osteosarcoma/genetics , Apoptosis/genetics , Blotting, Western , Bone Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Cell Survival/genetics , Computational Biology , Humans , MicroRNAs/metabolism , Neoplasm Invasiveness/genetics , Osteosarcoma/metabolism , Phenotype , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Transfection
15.
Virchows Arch ; 464(6): 701-7, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24756216

ABSTRACT

The objective of this study was to investigate the expression and clinical role of the spindle checkpoint kinase budding uninhibited by benzimidazole 1 (Bub1) in primary and metastatic advanced-stage ovarian serous carcinoma. BUB1 mRNA expression was analyzed in 178 tumors (88 effusions, 38 primary carcinomas, and 52 solid metastases) from 144 patients with advanced-stage disease using quantitative real-time polymerase chain reaction (PCR). Bub1 protein expression by Western blotting was studied in 63 carcinomas (30 effusions and 33 solid lesions). BUB1 mRNA expression at different anatomic sites was studied for association with clinicopathologic parameters, including chemotherapy resistance and survival. BUB1 mRNA was universally expressed in serous carcinomas, irrespective of anatomic site. BUB1 mRNA levels were uniformly low in six ovarian surface epithelium specimens analyzed for comparative purposes. Bub1 protein was expressed in 22/30 effusions and 28/33 solid lesions. BUB1 mRNA expression was significantly higher in chemo-naïve primary carcinomas and solid metastases compared to specimens obtained following neoadjuvant chemotherapy (p < 0.001) and was unrelated to chemotherapy exposure in effusions nor to chemoresponse or survival at any anatomic site. BUB1 mRNA levels in both effusions and solid lesions were strongly related to the mRNA levels of AURKA and AURKB previously studied in this cohort (p < 0.001 for both). Bub1 is widely expressed in primary and metastatic OC, suggesting a biological role in this cancer. BUB1 mRNA levels are lower following chemotherapy exposure in solid lesions, though its presence is unrelated to clinical behavior including response to chemotherapy and survival. BUB1 is co-expressed with AURKA and AURKB suggesting biological relationship between these spindle cell components.


Subject(s)
Aurora Kinase A/biosynthesis , Aurora Kinase B/biosynthesis , Cystadenocarcinoma, Serous/metabolism , Ovarian Neoplasms/metabolism , Protein Serine-Threonine Kinases/biosynthesis , Adult , Aged , Aged, 80 and over , Aurora Kinase A/genetics , Aurora Kinase B/genetics , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Blotting, Western , Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Protein Serine-Threonine Kinases/genetics , RNA, Messenger/analysis , Real-Time Polymerase Chain Reaction , Young Adult
16.
Endocrinology ; 155(5): 1643-52, 2014 May.
Article in English | MEDLINE | ID: mdl-24517226

ABSTRACT

The glucokinase-induced up-regulation of insulin receptor substrate 2 (IRS-2) plays an important role in ß-cell adaptive proliferation in response to high-fat diet-induced insulin resistance. This study aimed to investigate the role of IRS-2 in the proliferation of ß-cells after a 60% partial pancreatectomy. IRS-2-deficient (IRS-2(-/-)) mice or wild-type mice were subjected to a pancreatectomy (60% partial pancreatectomy) or a sham operation (Sham). The ß-cell proliferation and gene expression profiles of the islets were then assessed. Gene expression in islets from pancreatectomized and Sham C57BL/6J male mice was analyzed using a cDNA microarray analysis. To compare with ß-cell proliferation induced by a high-fat diet, Gck(+/-) mice subjected to a pancreatectomy were also analyzed. The IRS-2(-/-) mice exhibited ß-cell expansion and a significant increase in ß-cell proliferation after the pancreatectomy, compared with the Sham group. Although glucose-stimulated insulin secretion from islets was not impaired, IRS-2(-/-) mice manifested severe hyperglycemia after the pancreatectomy. The expression levels of Aurora kinase B, Cyclin A, and Cyclin B1 in the pancreatectomized islets were also enhanced in the IRS-2(-/-) mice. A gene set enrichment analysis suggested an association between the genes that were up-regulated in the pancreatectomized islets and those involved in M phase progression in the cell cycle. ß-Cell proliferation after a pancreatectomy was observed even in the Gck(+/-) mice. In conclusion, IRS-2 was not required for ß-cell proliferation but might be needed for functional ß-cell mass, after a pancreatectomy. A partial pancreatectomy in mice may be an attractive model for the development of new strategy for exploring the unique nature of ß-cell proliferation.


Subject(s)
Insulin Receptor Substrate Proteins/metabolism , Insulin-Secreting Cells/physiology , Pancreatectomy/adverse effects , Regeneration , Animals , Aurora Kinase B/biosynthesis , Aurora Kinase B/genetics , Aurora Kinase B/metabolism , Cell Proliferation , Crosses, Genetic , Cyclin A1/biosynthesis , Cyclin A1/genetics , Cyclin A1/metabolism , Cyclin B1/biosynthesis , Cyclin B1/genetics , Cyclin B1/metabolism , Diet, High-Fat/adverse effects , Glucokinase/genetics , Glucokinase/metabolism , Hyperglycemia/blood , Hyperglycemia/etiology , Hyperglycemia/metabolism , Hyperglycemia/pathology , Insulin/metabolism , Insulin Receptor Substrate Proteins/genetics , Insulin Secretion , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction , Up-Regulation
17.
Int J Clin Oncol ; 19(4): 622-8, 2014 Aug.
Article in English | MEDLINE | ID: mdl-23893130

ABSTRACT

BACKGROUND: Aurora B is a serine-threonine kinase and chromosomal passenger protein involved in the control of chromosome assembly and segregation during mitosis. Aberrant expression of Aurora B has been reported in some tumors, including lung and hepatocellular carcinoma (HCC). We investigated the role of Aurora B expression in both HCC and matched adjacent non-tumor tissue. METHODS: Sixty-three patients with HCC who underwent hepatic resection were enrolled in this study. Aurora B expression in tumor and non-tumor tissue was examined by use of quantitative reverse transcription-polymerase chain reaction. The patients were divided into high and low gene expression groups by median value, and clinicopathological data were compared between the two groups. RESULTS: Aurora B expression was significantly higher in tumor tissue than in non-cancerous tissue (P < 0.001). Disease-free survival was not significantly different between groups with high and low expression in the tumor tissues. For non-tumor tissues, disease-free survival of the low-expression group was significantly better than that of the high-expression group (P < 0.05). The gene expression level of Aurora B correlated with results from liver function tests, for example prothrombin time. CONCLUSION: Aurora B expression in non-cancerous tissues may be a prognostic factor for HCC.


Subject(s)
Aurora Kinase B/biosynthesis , Biomarkers, Tumor/biosynthesis , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Adult , Aged , Aurora Kinase B/genetics , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/pathology , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Humans , Liver/metabolism , Liver/pathology , Liver Neoplasms/pathology , Male , Middle Aged , Prognosis , Prothrombin Time
18.
Int J Oncol ; 41(4): 1475-85, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22858681

ABSTRACT

The Aurora family of kinases, play a fundamental role in cell division and are overexpressed in several cancers including colon. The activity of barasertib-hQPA, a selective inhibitor of Aurora-B kinase (ABK) was investigated in a range of preclinical models of gastrointestinal cancer. Treatment with barasertib-hQPA produced anti-proliferative and cytotoxic effects across a panel of human colorectal cancer (CRC) cell lines in vitro. Prodrug, barasertib [48-h subcutaneous (s.c.) infusion; 150 mg/kg/day] inhibited the growth of SW620, Colo205, HCT116 human colorectal tumor xenografts in nude mice significantly (Student's t-test, P<0.05, n=10-12 per group). Flow cytometric analysis of single cells from disaggregated barasertib-treated SW620 tumors revealed a decrease in phosphorylated histone H3 (phH3) and an increase in tumor cells with ≥4N DNA content P<0.05). The activity of barasertib was then examined in ApcMin/+ mice, a spontaneous model of early intestinal neoplasia. Macroscopic evaluation of the small intestine revealed that barasertib treatment [25 mg/kg intra-peritoneal (i.p.) Q1Dx4 each week for 3 weeks] of 8-week old ApcMin/+ mice produced a 39% reduction in macroadenoma number (P=0.02) and a 43% reduction in overall adenoma burden (P=0.02) compared with vehicle-treated controls. Quantification of microscopic adenomas revealed a >64% reduction in the number of adenomas spanning more than one villus. Histological analysis of these adenomas revealed a number of distinct changes in barasertib-treated ApcMin/+ mice, including a 94% reduction in the proportion of phospho-histone H3-positive cells (P<0.001) and a 53% reduction in the number of cells per adenoma (P=0.001). These results provide a scientific rationale for investigating ABK inhibitors as a treatment for intestinal cancer.


Subject(s)
Aurora Kinase B/biosynthesis , Cell Proliferation/drug effects , Colorectal Neoplasms/genetics , Gastrointestinal Neoplasms/genetics , Animals , Aurora Kinase B/antagonists & inhibitors , Aurora Kinase B/genetics , Colorectal Neoplasms/pathology , Gastrointestinal Neoplasms/pathology , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , Histones/genetics , Humans , Mice , Phosphorylation , Quinazolines/administration & dosage , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...